Markers of HIV Brain Disease under HAART: Validation in a Mouse Model

HAART 下 HIV 脑疾病的标志物：在小鼠模型中的验证

• 批准号: 8055797
• 负责人: MARY Jane POTASH
• 金额: $ 22.78万
• 依托单位: ST. LUKE'S-ROOSEVELT INST FOR HLTH SCIS
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2012-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055797
• 关键词: Affect; Animal Behavior; Animals; Anti-Retroviral Agents; Antiviral Agents; Behavioral; Biological; Biological Markers; Brain; Brain Diseases; Brain Pathology; Cells; Central Nervous System Diseases; Characteristics; Chronic; Cognitive; Cognitive deficits; Complement; Developed Countries; Development; Disease; Disease model; Equipment; Evaluation; Funding; Gene Expression; Gene Family; Genes; Genetic Transcription; HIV; HIV-1; Hand; Hand' s disease; Highly Active Antiretroviral Therapy; Human; Human Resources; Immune; Immunodeficient Mouse; Impaired cognition; Impairment; Infection; Inflammatory; Investments; Lead; Learning; Life; Macaca; Measures; Memory; Methods; Molecular Profiling; Mouse Strains; Mus; Neurocognitive; Neurons; Neuropathogenesis; Neuropathy; Oxidative Stress; Parents; Pathway interactions; Patient Representative; Patients; Peripheral; Persons; Physiology; Prevention; Problem behavior; Production; Proteins; Proviruses; Relative (related person); Request for Applications; Research; SIV; SNAP receptor; Testing; Time; Transgenic Mice; Validation; Viral Encephalitis; Viral Proteins; Virus; Work; antiretroviral therapy; base; behavior test; behavioral impairment; biological adaptation to stress; brain cell; clinically relevant; design; genome-wide; human tissue; immune function; long term memory; mild neurocognitive impairment; mouse model; neuropathology; overexpression; parent grant; programs; public health priorities; reconstitution; success

DESCRIPTION (provided by applicant): This Competitive Revision Application requests funds to expand the scope of the parent grant by adding a new objective, Aim 5, dedicated to behavioral/cognitive evaluations of HIV-1 infected mice. Our research is based on the hypothesis that there are core changes in brain physiology arising from long- lived HIV-1 infected cells that persist through existing therapies. Unabated production of viral proteins by these cells can cause cumulative inflammatory, antiviral, and oxidative stress reactions that affect neuronal function. We test this hypothesis in the parent grant in four Specific Aims to: 1) establish genome-wide brain gene expression profiles representative of patients with milder forms of HIV CNS disease; 2) identify biological pathways and biomarkers in the human brain characteristic of continuing mild HIV CNS disease in the presence of antiretroviral treatment; 3) validate selected markers of mild HIV CNS disease in brains of mice infected with chimeric, neuroinvasive HIV-1, EcoHIV, which causes mild neuropathological changes in mice similar to MND; 4) using this mouse model of MND, test the hypothesis that mild, chronic HIV CNS disease depends upon low level virus transcription unaffected by existing antiretroviral treatment. We have made significant progress in Aims 1-3. We found that EcoHIV infected mice develop mild cognitive impairments that last at least two months after infection and do not involve extensive neuropathology or viral encephalitis, similar to MND in human patients. With symptomatic cognitive impairment easily measured in mice, EcoHIV infection of mice now provides a more faithful representation of HIV-1 CNS disease in people. Behavioral testing in mice was not part of the parent grant (See Aims above). Here we propose to use the mechanism of the Competitive Revision Application to establish a behavioral component in the parent application. Because of its limited funding period, our application proposes primarily to establish and optimize behavioral testing methods, including investment in the required equipment and additional personnel. The behavioral testing will then be employed for the duration of the supplement for evaluation of MND markers that we have already identified. The following objectives are proposed, grouped under a new Specific Aim 5: A) To purchase equipment and test and select optimal behavioral tests measuring learning and short- and long-term memory for scoring behavioral/cognitive deficits induced by EcoHIV infection in mice; B) To determine the time course of the behavioral impairment relative to the course of peripheral EcoHIV infection and host immune status; C) To begin to examine brain pathology and expression of cellular markers of HIV-1 neuropathogenesis accompanying development of neurocognitive impairments in mice. We believe that the proposed behavioral component will significantly enrich the parent program by allowing experimental evaluation of HIV-1 neurocognitive disease, from identifying virus-induced genome- wide changes in the brain to verifying their importance in clinically relevant behavioral tests. PUBLIC HEALTH RELEVANCE: This application is proposed to supplement ongoing studies on the human and mouse gene products that associate with brain disease during HIV-1 infection. We have found that HIV-1 infected mice also develop problems in learning and memory and this study will systemically evaluate these behavioral problems in correlation to the ongoing studies on changes in brain cell gene expression in these animals.

描述（由申请人提供）：此竞争性修订申请书请求资金通过添加一个新的目标，AIM 5，专门针对HIV-1感染小鼠的行为/认知评估，以扩大父母赠款的范围。 我们的研究基于以下假设：长期存在的HIV-1感染细胞引起的脑生理核心变化，这些细胞通过现有疗法持续存在。这些细胞未减去病毒蛋白的产生可能会导致影响神经元功能的累积炎症，抗病毒和氧化应激反应。我们在父母赠款中以四个特定目的检验了这一假设：1）建立全基因组脑基因表达谱图代表患有较轻形式的HIV CNS疾病的患者； 2）在存在抗逆转录病毒治疗的情况下，在人脑中持续轻度艾滋病毒CNS疾病的生物学途径和生物标志物； 3）验证感染嵌合，神经侵袭性HIV-1，ECOHIV的小鼠大脑中轻度HIV CNS疾病的标记，该标记会导致类似于MND的小鼠的轻度神经病理学变化； 4）使用这种MND的小鼠模型，检验了一种假说，即轻度，慢性HIV CNS疾病取决于低水平的病毒转录不受现有抗逆转录病毒治疗的影响。 我们在目标1-3方面取得了重大进展。我们发现，EcoHIV感染的小鼠会出现轻度的认知障碍，至少在感染后两个月持续持续，并且不涉及广泛的神经病理学或病毒性脑炎，类似于人类患者的MND。由于在小鼠中很容易测量的有症状认知障碍，因此小鼠的Ecohiv感染现在可以更忠实地表示患者的HIV-1 CNS疾病。小鼠的行为测试不是父母赠款的一部分（请参见上面的目的）。在这里，我们建议使用竞争性修订应用程序的机制来在父申请中建立行为组成部分。由于其资助期限有限，我们的申请主要是建立和优化行为测试方法，包括对所需设备和其他人员的投资。然后，将在补充期间使用该行为测试来评估我们已经确定的MND标记。提出了以下目标，分组为新的特定目的5：a）购买设备并选择最佳的行为测试，以测量学习和短期记忆，以评估小鼠ecohiv引起的行为/认知缺陷； b）确定相对于周围生态感染和宿主免疫状态的行为障碍的时间过程； c）开始检查伴随小鼠神经认知障碍发展的HIV-1神经病发生的细胞标志物的表达。 我们认为，提出的行为成分将通过允许对HIV-1神经认知疾病的实验评估，从识别病毒诱导的大脑中的基因组变化来验证其在临床相关行为测试中的重要性，从而显着丰富父母计划。 公共卫生相关性：提出了该应用来补充对HIV-1感染期间与脑疾病相关的人类和小鼠基因产品的正在进行的研究。我们发现，HIV-1感染的小鼠还会在学习和记忆中出现问题，这项研究将系统地评估这些行为问题，与对这些动物中脑细胞基因表达的变化的持续研究相关。